This is a retrospective cohort study of 893 kidney transplant recipients between 2004-2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing to investigate the relationship between HLA molecular mismatches and T-cell mediated rejection (TCMR). 277 patients developed TCMR and 134 developed only borderline changes suggestive of TCMR on at least one biopsy. In multivariable analyses, only the PIRCHE-II scores (Predicted Indirectly ReCognizable HLA Epitopes by recipient HLA class II molecules algorithm) for HLA-DRB1 and HLA-DQB1 were independently associated with the occurrence of TCMR and with allograft failure; this was not the case for HLA class I molecules. If restricted to rejection episodes within the first 3 months after transplantation, only the T-cell epitope targets originating from the donor's HLA-DRB1 and HLA-DQB1, but not class I molecules, were associated with the early acute TCMR. Also, the median number of PIRCHE-II scores for HLA class II was statistically different between the patients with TCMR compared to the patients without TCMR (129, IQR=60-240; vs. 201, IQR=96-298; p<0.0001, respectively). These differences were not observed for class I PIRCHE-II scores.